Optimized Photoactivatable Lipid Nanoparticles Enable Red Light Triggered Drug Release

Abstract

Encapsulation of small molecule drugs in long‐circulating lipid nanoparticles (LNPs) can reduce toxic side effects and enhance accumulation at tumor sites. A fundamental problem, however, is the slow release of encapsulated drugs from these liposomal systems at the disease site resulting in limited therapeutic benefit. Methods to trigger release at specific sites are highly warranted. Here, it is demonstrated that incorporation of ultraviolet (UV‐A) or red‐light photoswitchable‐phosphatidylcholine analogs (AzoPC and redAzoPC) in conventional LNPs generates photoactivatable LNPs (paLNPs) having comparable structural integrity, drug loading capacity, and size distribution to the parent DSPC‐cholesterol liposomes. It is shown that 65–70% drug release (doxorubicin) can be induced from these systems by irradiation with pulsed light based on trans‐to‐cis azobenzene isomerization. In vitro it is confirmed that paLNPs are non‐toxic in the dark but convey cytotoxicity upon irradiation in a human cancer cell line. In vivo studies in zebrafish embryos demonstrate prolonged blood circulation and extravasation of paLNPs comparable to clinically approved formulations, with enhanced drug release following irradiation with pulsed light. Conclusively, paLNPs closely mimic the properties of clinically approved LNPs with the added benefit of light‐induced drug release making them promising candidates for clinical development.

Photophosphatidylserine Guides Natural Killer Cell Photoimmunotherapy via Tim-3

“…In addition, our findings indicate that phoPS activation/inactivation of Tim-3 is relatively defective. Fortunately, fast, high-yield transformed and red-shifted azobenzene derivatives have been developed. − This makes it possible to design a novel type of “ phoPS ” that blocks Tim-3 in the trans form and activates Tim-3 in the cis form. Given this conception, phoPS would be an inhibitor/activator in literally optical controlling NK cell functions.…”

Demolish and Rebuild: Controlling Lipid Self-Assembly toward Triggered Release and Artificial Cells

“…Commonly explored photochemical activation strategies include photoisomerization with azobenzene units or photocleavable linkers, such as o -nitrobenzyl moieties. , Witzigmann and co-workers recently reported an optimized photoactivatable liposomal delivery system based on cis – trans -azobenzene isomerization. Irradiation induced 65%–70% Dox release from ∼50 nm lipid nanoparticles within 24 h . Azobenzene isomerization has also been exploited for the development of photoresponsive micelles that allowed spectroscopic analysis of the physical behavior of antimicrobial peptides within a membrane environment, as reported by Roberson et al The o -nitrobenzyl moiety has been employed to develop liposomes with dual responsive release capabilities by incorporating both light-sensitive and acid-sensitive units into a single system .…”

Optical Control of Membrane Fluidity Modulates Protein Secretion

“…While optogenetics is based on genetically encoded photoreceptors, photopharmacology relies on synthetic molecular photoswitches, such as azobenzenes (Beharry and Woolley, 2011; Hüll et al, 2018; Szymański et al, 2013). Photoswitchable lipids have emerged as versatile tools to control defined protein-membrane interactions in vivo (Morstein et al, 2019, 2021a) as well as membrane mechanics in model membranes(Chander et al, 2021; Doroudgar et al, 2021; Pernpeintner et al, 2017). If these lipids could be integrated into cellular membranes in sufficient quantities, they could meet a long-standing need in the field to control biophysical parameters of membranes remotely and with high spatiotemporal resolution within living systems.…”